Estrogen receptor β and <i>TMPRSS2-ERG</i> expression association with clinical outcomes in metastatic hormone-sensitive prostate cancer.
Authors: Caterina Aversa, Natalia Jiménez, Mercedes Marin, Laura Ferrer-Mileo, Oscar Reig, Leonardo Rodriguez-Carunchio, Albert Font, Alejo Rodriguez-Vida, Montserrat Domenech-Santasusana, Mariona Figols, Miguel Angel Climent Duran, Sara Cros Costa, Isabel Chirivella, Daniel Herrero Rivera, Enrique Gonzalez -Billalabeitia, Daniel Jiménez-Peralta, Joan Carles, Cristina Suárez, Aleix Prat, Begona Mellado
Journal: Journal of Clinical Oncology (2022)

5077 Background: TMPRSS2-ERG fusion has been associated with estrogen receptor (ER) signalling in prostate cancer (PC). The isoform beta of ER (ERβ), encoded by ESR2, is considered anti-proliferative and tumor-suppressive. In preclinical studies, ESR2 has shown an inhibitory role towards TMPRSS2-ERG, resulting in decreased proliferation and tumor regression. In this clinical series, we sought to investigate the correlation between TMPRSS2-ERG and ESR2 expression and its impact on clinical outcomes in a cohort of patients (pts) with metastatic hormone-sensitive PC (mHSPC). Methods: This is a multicenter retrospective biomarker study. TMPRSS2-ERG and ESR2 were tested in total mRNA from FFPE tumor samples by nCounter platform (Nanostring Technologies). TMPRSS2-ERG and ESR2 expression were correlated with castration-resistant PC free survival (CRPC-FS) and overall survival (OS) by Kaplan Meier and multivariate Cox modeling. R (v.3.6.3) software was used for statistical analysis. Results: 218 mHSPC pts were included: 125 received androgen deprivation therapy (ADT) with Docetaxel and 93 ADT alone. Median age was 66.4 years (range 46.3-84.6), 75.7% ( N= 165) presented with de novo mHSPC, 15.1% ( N= 33) had visceral metastasis and 68.3% ( N= 149) had high volume disease. Median follow-up was 38.8 months (m) (range 6.7-223.5) and 189 pts (86.7%) developed CRPC. Five pts were excluded due to lack of follow-up. Median time to CRPC was 18.8 m (95% CI 15.8-20.5) and median OS was 48.8 m (95% CI 43.2-59.1). Pts were grouped according to TMPRSS2-ERG fusion detection in TE positive (TE+) ( N= 108, 49.5%) and TE negative (TE-) ( N= 110, 50.5%) and according to ESR2 expression levels segregated into tertiles in ESR2 high (ESR2+) ( N= 74, 33.9%) or ESR2 low-mid (ESR2-) ( N= 144, 66.1%). TE+ status was associated to higher ESR2 levels ( P= 0.03). The TE+/ESR2+ group showed longer CRPC-FS and OS, compared with the other groups, as shown in the table. TE+/ESR2 expression was independently associated with longer CRPC-FS (HR 0.3, 95% CI 0.2-0.5, P&lt; 0.001) and OS (HR 0.3, 95% CI 0.2-0.5, P&lt; 0.001). Moreover, a significant interaction between treatment (ADT vs ADT+Docetaxel) and TE+/ESR2+ status related to CRPC-FS was found (HR: 0.38, P= 0.014), suggesting that TE+/ESR2+ pts may benefit more from ADT than from the combination of ADT+Docetaxel. Conclusions: Our study suggests a protective role of ESR2 within a subgroup of mHSPC pts characterized by TMPRSS2-ERG fusion, which warrants further investigation of ESR2 as a prognostic factor, for treatment selection and as a potential pathway for targeted treatment in PC. [Table: see text]